Neuroblastoma and treatment-related myelodysplasia/leukemia: The Memorial Sloan-Kettering experience and a literature review

Purpose: To assess treatment-related myelodysplasia/leukemia (t-AML) in neu roblastoma patients by a review of the Memorial Sloan-Kettering Cancer Cent er (MSKCC) data and the literature. Patients and Methods: We studied 380 previously untreated and treated MSKCC patients. Low-risk patients received no cytotoxic therapy. High-risk patie nts received the N4, N5, or N6 regimens. Dosing per cycle and cumulative do sing of leukemogenic agents peaked with N6, which included four cycles of c yclophosphamide 4,200 mg/m(2) and doxorubicin 75 mg/m(2), plus three cycles of cisplatin 200 mg/m(2) and etoposide 600 mg/m(2). We reviewed the litera ture. Results: t-AML occurred in six MSKCC patients, which included three of 53 p atients in whom the only chemotherapy consisted of N6, and three patients t reated for relapsed or refractory neuroblastoma; no case of leukemia emerge d among the 50 low-risk patients. Four cases were found incidentally in rou tine follow-up bone marrow tests. The 36-month cumulative incidence of t-AM L in the N6 cohort was 7% (95% confidence interval, 0 to 15), Published dat a parallel the MSKCC experience in that t-AML after neuroblastoma was once rare but has become less so since the mid-1980s, when the intensified use o f topoisomerase-II inhibitors and alkylators first gained wide acceptance a nd produced better response rates and longer survival. Conclusion: Neuroblastoma itself is not associated with a host susceptibili ty to leukemia. However, current neuroblastoma treatment programs that use high-dose cyclophosphamide, cisplatin, and topoisomerase-II inhibitors may entail a considerable risk for t-AML, The incidence of t-AML in neuroblasto ma patients may be underestimated because treatment and clinical factors ca n mask its presence. Efforts to devise effective but less leukemogenic trea tment for neuroblastoma or to truncate leukemogenic therapy, eg, by exploit ing molecular techniques for the early identification of complete remission , are warranted. (C) 1998 by American Society of Clinical Oncology.